Abstract
ObjectiveDNA aberrations that cause colorectal cancer (CRC) occur in multiple steps that involve microsatellite instability (MSI) and chromosomal instability (CIN). Herein, we studied CRCs from AA patients for their CIN and MSI status.Experimental DesignArray CGH was performed on 30 AA colon tumors. The MSI status was established. The CGH data from AA were compared to published lists of 41 TSG and oncogenes in Caucasians and 68 cancer genes, proposed via systematic sequencing for somatic mutations in colon and breast tumors. The patient-by-patient CGH profiles were organized into a maximum parsimony cladogram to give insights into the tumors' aberrations lineage.ResultsThe CGH analysis revealed that CIN was independent of age, gender, stage or location. However, both the number and nature of aberrations seem to depend on the MSI status. MSI-H tumors clustered together in the cladogram. The chromosomes with the highest rates of CGH aberrations were 3, 5, 7, 8, 20 and X. Chromosome X was primarily amplified in male patients. A comparison with Caucasians revealed an overall similar aberration profile with few exceptions for the following genes; THRB, RAF1, LPL, DCC, XIST, PCNT, STS and genes on the 20q12-q13 cytoband. Among the 68 CAN genes, all showed some level of alteration in our cohort.ConclusionChromosome X amplification in male patients with CRC merits follow-up. The observed CIN may play a distinctive role in CRC in AAs. The clustering of MSI-H tumors in global CGH data analysis suggests that chromosomal aberrations are not random.
Highlights
Numerous studies have investigated the mechanisms of DNA changes leading to colorectal cancer (CRC), which is the third most common cancer in the US [1]
The observed chromosomal instability (CIN) may play a distinctive role in CRC in AAs
The clustering of microsatellite instability (MSI)-H tumors in global Comparative genomic hybridization (CGH) data analysis suggests that chromosomal aberrations are not random
Summary
Numerous studies have investigated the mechanisms of DNA changes leading to colorectal cancer (CRC), which is the third most common cancer in the US [1]. The initiation and progression of CRC is associated with alterations in the function of oncogenes and tumor suppressor genes. Three major mechanisms of genomic instability in CRC have been described: microsatellite instability (MSI), chromosomal instability (CIN), and more recently CpG island methylation phenotype (CIMP). Excessive promoter methylation of hundreds of genes results in the CIMP is part of the epigenetic instability in CRC. In MSI, which occurs in about 15% of CRC, DNA mismatch repair genes are either mutated or methylated leading to tumors with a microsatellite instability phenotype (denoted MSI-High, MSI-H, or MIN) [3]
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